Duloxetine hydrochloride, (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloric acid salt, is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. Duloxetine hydrochloride is used for the treatment of stress urinary incontinence (“SUI”), depression, and pain management and is commercially available as CYMBALTA®. Duloxetine hydrochloride has the following chemical structure:

U.S. Pat. No. 5,023,269 (“'269 patent”) discloses a class of 3-aryloxy-3-substituted propanamines, including duloxetine, as well as pharmaceutically acceptable acid addition salts thereof. See '269 patent, col. 1, 11. 27-58. The '269 patent also discloses a general process for preparing compounds of the class, and exemplifies, inter alia, the preparation of duloxetine oxalate. See '269 patent, col. 7, 11. 5-30 (example 2). In the '269 patent, duloxetine is prepared by reacting N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with fluoronaphthalene, followed by demethylation with phenyl chloroformate or trichloroethyl chloroformate and basic hydrolysis. See '269 patent, col. 6, 1. 13 to col. 7, 1. 30 (examples 1 and 2).
European patent No. 457559 and U.S. Pat. Nos. 5,491,243 (“'243 patent”) and 6,541,668 provide synthetic routes for the preparation of duloxetine. The conversion of duloxetine to its hydrochloride salt is disclosed in the '243 patent, as well as in Wheeler W. J., et al., J. Label. Cpds. Radiopharm., 1995, 36, 312. In both the '243 patent and the Wheeler article, the conversion of duloxetine to its hydrochloride salt is performed in ethyl acetate under specified conditions.
Like any synthetic compound, duloxetine hydrochloride can contain extraneous compounds or impurities. These impurities may be, for example, starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in duloxetine hydrochloride, or any active pharmaceutical ingredient (“API”), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The purity of an API produced in a manufacturing process is critical for commercialization. The U.S. Food and Drug Administration (“FDA”) requires that process impurities be maintained below set limits. For example, in its ICH Q7A guidance for API manufacturers, the FDA specifies the quality of raw materials that may be used, as well as acceptable process conditions, such as temperature, pressure, time, and stoichiometric ratios, including purification steps, such as crystallization, distillation, and liquid-liquid extraction. See ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7A, Current Step 4 Version (Nov. 10, 2000).
The product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product. At certain stages during processing of an API, such as duloxetine hydrochloride, it must be analyzed for purity, typically, by high performance liquid chromatography (“HPLC”) or thin-layer chromatography (“TLC”), to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The FDA requires that an API is as free of impurities as possible, so that it is as safe as possible for clinical use. For example, the FDA recommends that the amounts of some impurities be limited to less than 0.1 percent. See ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7A, Current Step 4 Version (Nov. 10, 2000).
Generally, side products, by-products, and adjunct reagents (collectively “impurities”) are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. See Strobel, H. A., et al., CHEMICAL INSTRUMENTATION: A SYSTEMATIC APPROACH, 953, 3d ed. (Wiley & Sons, New York 1989). Once a particular impurity has been associated with a peak position, the impurity can be identified in a sample by its relative position in the chromatogram, where the position in the chromatogram is measured in minutes between injection of the sample on the column and elution of the impurity through the detector. The relative position in the chromatogram is known as the “retention time.”
The retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners often use “relative retention time” (“RRT”) to identify impurities. See supra Strobel at 922. The RRT of an impurity is calculated by dividing the retention time of the impurity by the retention time of a reference marker. The reference marker may be the API in which the impurity is present, or may be another compound that is either present in or added to the sample. A reference marker should be present in the sample in an amount that is sufficiently large to be detectable, but not in an amount large enough to saturate the column.
Those skilled in the art of drug manufacturing research and development understand that a relatively pure compound can be used as a “reference standard.” A reference standard is similar to a reference marker, except that it may be used not only to identify the impurity, but also to quantify the amount of the impurity present in the sample.
A reference standard is an “external standard,” when a solution of a known concentration of the reference standard and an unknown mixture are analyzed separately using the same technique. See supra Strobel at 924; Snyder, L. R., et al., INTRODUCTION TO MODERN LIQUID CHROMATOGRAPHY, 549, 2d ed. (John Wiley & Sons, New York 1979). The amount of the impurity in the sample can be determined by comparing the magnitude of the detector response for the reference standard to that for the impurity. See U.S. Pat. No. 6,333,198, hereby incorporated by reference.
The reference standard can also be used as an “internal standard,” i.e., one that is directly added to the sample in a predetermined amount. When the reference standard is an internal standard, a “response factor,” which compensates for differences in the sensitivity of the detector to the impurity and the reference standard, is used to quantify the amount of the impurity in the sample. See supra Strobel at 894. For this purpose, the reference standard is added directly to the mixture, and is known as an “internal standard.” See supra Strobel at 925; Snyder at 552.
The technique of “standard addition” can also be used to quantify the amount of the impurity. This technique is used where the sample contains an unknown detectable amount of the reference standard. In a “standard addition,” at least two samples are prepared by adding known and differing amounts of the internal standard. See supra Strobel at 391-393; Snyder at 571-572. The proportion of the detector response due to the reference standard present in the sample can be determined by plotting the detector response against the amount of the reference standard added to each of the samples, and extrapolating the plot to zero. See supra Strobel at 392, FIG. 11.4.
Duloxetine hydrochloride may contain the impurity 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene. There is, therefore, a need in the art to detect, isolate, and remove the 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene impurity from samples of duloxetine hydrochloride.